Challenges, Recent Advances and Perspectives in the Treatment of Human Cytomegalovirus Infections

Abstract

Human cytomegalovirus (HCMV) is ubiquitous worldwide and elicits global health problems. The diseases associated with HCMV are a serious threat to humans, especially for the sick, infant, elderly and immunocompromised/immunodeficient individuals. Although traditional antiviral drugs (e.g., ganciclovir, valganciclovir, cidofovir, foscarnet) can be used to treat or prevent acute HCMV infections, their efficacy is limited because of toxicity, resistance issues, side effects and other problems. Fortunately, novel drugs (e.g., letermovir and maribavir) with less toxicity and drug/cross-resistance have been approved and put on the market in recent years. The nucleic acid-based gene-targeting approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPRs)/CRISPRs-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) have been investigated to remove both lytic and latent CMV in vitro and/or in vivo. Cell therapy including the adoptive T cell therapy (ACT) and immunotherapy have been tried against drug-resistant and recurrent HCMV in patients receiving hematopoietic stem cell transplantation (HSCT) or solid organ transplant (SOT), and they have also been used to treat glioblastoma (GBM) associated with HCMV infections. These newly developed antiviral strategies are expected to yield fruitful results and make a significant contribution to the treatment of HCMV infections. Despite this progress, the nucleic acid-based gene-targeting approaches are still under study for basic research, and cell therapy is adopted in a small study population size or only successful in case reports. Additionally, no current drugs have been approved to be indicated for latent infections. Therefore, the next strategy is to develop antiviral strategies to elevate efficacy against acute and/or latent infections and overcome challenges such as toxicity, resistance issues, and side effects. In this review, we would explore the challenges, recent advances and perspectives in the treatment of HCMV infections. Furthermore, the suitable therapeutic strategies as well as the possibility for compassionate use would be evaluated.

Infectious Myelopathies

“…Myelitis is often preceded by painful cutaneous vesicular lesions in a dermatomal pattern but can present at the same time as the cutaneous lesions or occasionally without any vesicular skin eruptions 69,70 . Like HSV-2 and CMV, VZV also can cause a syndrome of acute radiculomyelitis of the conus (sometimes called Elsberg syndrome ) 70,71 . VZV angiopathy is a rare complication that can result in spinal cord infarction.…”

“…The duration of treatment varies. Newer antiviral drugs, including letermovir and maribavir, were US Food and Drug Administration (FDA) approved for CMV infection, and adoptive T-cell therapies have shown promise in posttransplantation patients with CMV infection 71 …”

Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers

“…Currently available drugs for the treatment of HCMV infections include pharmacological inhibitors of functions of the viral DNA polymerase (i.e., ganciclovir, its oral prodrug valganciclovir, cidofovir and foscarnet), the viral terminase complex (letermovir) and, approved very recently, the viral protein kinase (maribavir). Despite the great benefit that these anti-HCMV drugs present for the management of HCMV infections, they are limited by undesirable complications, such as the development of viral drug resistance, restrictions in oral bioavailability in several cases, as well as sometimes serious side effects [ 6 , 7 ]. Consequently, novel therapeutic strategies against HCMV are the focus of current research efforts, including the exploration of novel targeting options, using both direct-acting antivirals (DAAs) and host-directed antivirals (HDAs) [ 7 , 8 , 9 , 10 , 11 ].…”

“…Despite the great benefit that these anti-HCMV drugs present for the management of HCMV infections, they are limited by undesirable complications, such as the development of viral drug resistance, restrictions in oral bioavailability in several cases, as well as sometimes serious side effects [ 6 , 7 ]. Consequently, novel therapeutic strategies against HCMV are the focus of current research efforts, including the exploration of novel targeting options, using both direct-acting antivirals (DAAs) and host-directed antivirals (HDAs) [ 7 , 8 , 9 , 10 , 11 ].…”

“…Recently, we characterized pharmacological inhibitors of cyclin-dependent kinases (CDKs) as very potent anti-HCMV investigational candidates and suggested CDK-directed targeting as a next-generation developmental strategy towards new antiviral small molecules [ 12 , 13 , 14 , 15 ]. In this ongoing line of research, we focused on both host CDKs, such as CDK7 (i.e., using the selective developmental inhibitor LDC4297 [ 16 ]), as well as the viral CDK ortholog pUL97 (vCDK; i.e., using the clinically approved maribavir/MBV and chemically distinct investigational pUL97 inhibitors [ 7 , 17 , 18 ]). These findings have to be seen in the context of regulatory studies highlighting the role of vCDK/pUL97 and CDKs for HCMV replication and virus–host interaction [ 17 ].…”